Diabetic retinopathy (DR) is currently the leading cause of vision loss in working-aged adults. With the anticipated growth of the diabetic population, the number of visually impaired diabetic people who cannot work or care for themselves will continue to be a major public health concern. Diabetes is known to cause alterations in the retinal microvasculature and tissue that can progressively lead to visual impairment. Currently, prevention of vision loss due to DR requires early diagnosis, regular monitoring, and timely therapeutic intervention. However, a key impediment is distinguishing diabetic individuals who will develop retinopathy and progress to vision-threatening diabetic macular edema or proliferative DR. Furthermore, it is not known why anti-vascular endothelium growth factor treatment of diabetic macular edema is effective in improving vision of only some individuals. Since multiple concomitant factors likely contribute to the pathophysiology of DR, single biomarkers of retinal structure have had limited success in predicting DR progression and treatment outcome. The current research proposal will overcome this limitation by an innovative approach of comprehensive and comparative characterization of both anatomical and physiological ocular biomarkers. The specific aims are to identify ocular biomarkers of microvascular, neural, and metabolic function that are predictive of development, progression, and treatment outcome of DR. These ocular biomarkers will be obtained by non-invasive multimodal optical imaging technologies. The findings will also provide insight into how microvascular, neural and metabolic biomarkers interact synergistically in contributing to the development of DR and other diabetes complications. Future incorporation of the identified ocular biomarkers into clinical practice will aid in prevention of visual impairment, thereby significantly impacting the quality of life of diabetic people.